Many types of hematological and solid cancers are associated with new blood vessel formation, a process known as angiogenesis. Several of the mechanisms involved in tumor-induced angiogenesis have been elucidated. The most direct of these mechanisms is the secretion by the tumor cells of cytokines with angiogenic properties, including tumor necrosis factor α (TNF-α).
A variety of other diseases and disorders are also associated with, or characterized by, undesired angiogenesis. For example, enhanced or unregulated angiogenesis has been implicated in a number of diseases and medical conditions including, but not limited to, inflammatory diseases, allergic diseases, and autoimmune diseases. Examples of such diseases and conditions include, but are not limited to: scleroderma, Sjögren syndrome, systemic lupus erythematosus, and solid and hematological cancers.
Certain 4′-arylmethoxy isoindoline compounds, such as 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, and methods of use and pharmaceutical compositions thereof have been described in U.S. Pat. No. 8,518,972, the entirety of which is incorporated herein by reference. The afore-mentioned compound has been shown to be potent in treating cancer, disorders associated with angiogenesis, an immunodeficiency disorder, scleroderma, lupus, or Sjögren syndrome, or a TNFα related disorder.
After administration of pharmacologically active compounds, some of the them are absorbed and directly produce physiological effects, whereas others must undergo a series of metabolic reactions and are converted to active metabolite that can retain the affinity of the pre-metabolic drug for the pharmacological target. Thus, the chemical structure of pharmacologically active metabolites may differ from the compounds originally administered.
In practice, it is believed that the drug effect and the efficacy of a metabolite may differ from its pre-metabolic form, e.g., in the affinity to the pharmacological target, the functional activity, the plasma protein binding, the membrane permeability, or pharmacokinetics. This can have consequences regarding reduced side effects, improved drug safety, drug potency, and drug effectiveness and proves that active metabolites are not merely another form of pre-metabolic compounds, but constitute at least in some instances new and unique substances. It is believed that the differences between a metabolite and its pre-metabolic compound in side effects, drug safety, drug potency and drug effectiveness may directly influence the pharmacologic dosing regimen of the metabolite as a drug itself.
Due to the fact that the chemical structure of active metabolites differs from the compounds originally administered, the metabolite may possess different physicochemical properties which can open the door to new routes of administration. For example, it may be possible to provide a transdermal therapy in order to circumvent liver-passage.
There may be circumstances where it is desired to reduce the administration of the pre-metabolic drug or where its administration is even contraindicated. For example, in patients where metabolism of the pre-metabolic drug is inhibited, either because of the patient's hepatic enzymatic activity levels or because of ingestion of substances that have inhibitory effects on hepatic metabolism, particularly on members of the cytochrome P450 family of oxidizing enzymes (CYPS) such as, e.g., CYP3A4, patients may be advised to reduce the amount of the pre-metabolic drug being taken.
Thus, there remains a need for identification and development of additional 4′-arylmethoxy isoindoline compounds and for identification and development of active metabolites of such 4′-arylmethpxy isoindoline compounds, which may have the same or even improved activity compared to the pre-metabolic compound. Compounds and pharmaceutical compositions are desired that can be used for the treatment and prevention of disorders and conditions while even improving the effects associated with the administration of, for example, a pre-metabolic form of a compound or improving bioavailability characteristics and improving potential for immediate action and long-term treatment regimens.